U.S. patent application number 12/469951 was filed with the patent office on 2009-12-03 for processes and compounds for the preparation of normorphinans.
This patent application is currently assigned to Mallinckrodt Inc.. Invention is credited to Gary L. Cantrell, Christopher W. Grote, Robert E. Halvachs, Tao Jiang, Frank W. Moser, Peter X. Wang.
Application Number | 20090299069 12/469951 |
Document ID | / |
Family ID | 40933454 |
Filed Date | 2009-12-03 |
United States Patent
Application |
20090299069 |
Kind Code |
A1 |
Wang; Peter X. ; et
al. |
December 3, 2009 |
Processes and Compounds for the Preparation of Normorphinans
Abstract
The invention generally provides processes and intermediate
compounds useful for the production of normorphinans and
derivatives of normorphinans.
Inventors: |
Wang; Peter X.; (Clarkson
Valley, MO) ; Moser; Frank W.; (Arnold, MO) ;
Cantrell; Gary L.; (Troy, MO) ; Jiang; Tao;
(St. Louis, MO) ; Halvachs; Robert E.;
(Belleville, IL) ; Grote; Christopher W.; (Webster
Groves, MO) |
Correspondence
Address: |
Mallinckrodt Inc.
675 McDonnell Boulevard
HAZELWOOD
MO
63042
US
|
Assignee: |
Mallinckrodt Inc.
Hazelwood
MO
|
Family ID: |
40933454 |
Appl. No.: |
12/469951 |
Filed: |
May 21, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61056079 |
May 27, 2008 |
|
|
|
Current U.S.
Class: |
546/46 |
Current CPC
Class: |
A61P 29/00 20180101;
C07D 489/08 20130101; A61P 25/00 20180101; C07D 221/28 20130101;
A61P 25/04 20180101; C07D 489/02 20130101 |
Class at
Publication: |
546/46 |
International
Class: |
C07D 489/08 20060101
C07D489/08 |
Claims
1. A compound comprising Formula 21a: ##STR00024## wherein: R.sup.1
and R.sup.2 are independently chosen from hydrogen, OH, NH.sub.2,
SH, CF.sub.3, hydrocarbyl, substituted hydrocarbyl, alkyl ketal,
alkyl thiol ketal, and alkyl dithiol ketal, wherein when R.sup.1
and R.sup.2 are different they form an epimeric pair, and wherein
R.sup.1 and R.sup.2 together may form a group chosen from .dbd.O,
.dbd.S, cycloalkyl ketal, cycloalkyl thiol ketal, and cycloalkyl
dithiol ketal; R.sup.3 is chosen from hydrogen, halogen, OH,
NH.sub.2, CN, CF.sub.3, SO.sub.2R.sup.8, hydrocarbyl, and
substituted hydrocarbyl; R.sup.4 and R.sup.5 are independently
chosen from --(CH.sub.2).sub.nCH.sub.3 and CH.sub.3; R.sup.8 is
chosen from hydrocarbyl and substituted hydrocarbyl; X is halogen;
Y is chosen from an aryl group, a benzyl group, an acyl group, a
formyl ester, an alkoxycarbonyl group, a benzyloxycarbonyl group,
an alkylamidocarbonyl group, a trialkylsilyl group, an
alkylsulfonyl group, and an aryl sulfonyl group; and n is an
integer from 1 to 8.
2. The compound of claim 1, wherein: R.sup.1, R.sup.2, and
R.sup.3are each hydrogen; R.sup.4 and R.sup.5 are each CH.sub.3; X
is bromine; and Y is chosen from --Si(CH.sub.3).sub.3,
--COCH.sub.3, --CO.sub.2CH.sub.2CH.sub.3, and
--SO.sub.2CH.sub.3.
3. The compound of claim 1, wherein the optical activity of the
compound is (+) or (-), and the configuration of C-5, C-13, and
C-9, respectively, of the compound may be RRR, RRS, RSR, RSS, SRR,
SRS, SSR, or SSS, provided that the C-15 and the C-16 carbons are
both either on the alpha face or the beta face of the molecule.
4. A compound comprising Formula 25: ##STR00025## wherein: R.sup.1
and R.sup.2 are independently chosen from hydrogen, OH, NH.sub.2,
SH, CF.sub.3, hydrocarbyl, substituted hydrocarbyl, alkyl ketal,
alkyl thiol ketal, and alkyl dithiol ketal, wherein when R.sup.1
and R.sup.2 are different they form an epimeric pair, and wherein
R.sup.1 and R.sup.2 together may form a group chosen from .dbd.O,
.dbd.S, cycloalkyl ketal, cycloalkyl thiol ketal, and cycloalkyl
dithiol ketal; R.sup.3 is chosen from hydrogen, halogen, OH,
NH.sub.2, CN, CF.sub.3, SO.sub.2R.sup.8, hydrocarbyl, and
substituted hydrocarbyl; R.sup.6 is chosen from hydrogen, an alkyl
group, an allyl group, a cycloalkylmethyl group, an aryl group, a
benzyl group, and C(O).sub.nR.sup.7; R.sup.7 is chosen from an
alkyl group, an aryl group, and a benzyl group; R.sup.8 is chosen
from hydrocarbyl and substituted hydrocarbyl; X is halogen; and n
is an integer from 1 to 2.
5. The compound of claim 4, wherein: R.sup.1, R.sup.2, and R.sup.3
are each hydrogen; R.sup.6 is chosen from hydrogen, CH.sub.3,
--COCH.sub.3, and --CO.sub.2CH.sub.2CH.sub.3; and X is bromine.
6. The compound of claim 4, wherein the optical activity of the
compound is (+) or (-), and the configuration of C-5, C-13, C-14,
and C-9, respectively, is chosen from RRRR, RRSR, RRRS, RRSS, RSRR,
RSSR, RSRS, RSSS, SRRR, SRSR, SRRS, SRSS, SSRR, SSSR, SSRS, and
SSSS, provided that the C-15 and the C-16 carbons are both either
on the alpha face or the beta face of the molecule.
7. A process for the preparation of compound 21, the process
comprising the following reaction scheme: ##STR00026## wherein:
R.sup.1 and R.sup.2 are independently chosen from hydrogen, OH,
NH.sub.2, SH, CF.sub.3, hydrocarbyl, substituted hydrocarbyl, alkyl
ketal, alkyl thiol ketal, and alkyl dithiol ketal, wherein when
R.sup.1 and R.sup.2 are different they form an epimeric pair, and
wherein R.sup.1 and R.sup.2 together may form a group chosen from
.dbd.O, .dbd.S cycloalkyl ketal, cycloalkyl thiol ketal, and
cycloalkyl dithiol ketal; R.sup.3 is chosen from hydrogen, halogen,
OH, NH.sub.2, CN, CF.sub.3, SO.sub.2R.sup.8, hydrocarbyl, and
substituted hydrocarbyl; R.sup.4 and R.sup.5 are independently
chosen from --(CH.sub.2).sub.nCH.sub.3, and CH.sub.3; R.sup.8 is
chosen from hydrocarbyl and substituted hydrocarbyl; X is halogen;
Y is chosen from an aryl group, a benzyl group, an acyl group, a
formyl ester, an alkoxycarbonyl group, a benzyloxycarbonyl group,
an alkylamidocarbonyl group, a trialkylsilyl group, an
alkylsulfonyl group, and an aryl sulfonyl group; YX is chosen from
R.sub.mSiX, POX.sub.3, (RCO).sub.2O, RCOX, RSO.sub.2X, and
(RSO.sub.2).sub.2O; m is an integer from 1 to 3; and n is an
integer from 1 to 8.
8. The process of claim 7, wherein: YX is chosen from
(CH.sub.3).sub.3SiCl, POCl.sub.3, (CH.sub.3CO).sub.2O,
CH.sub.3COCl, CH.sub.3SO.sub.2Cl, CH.sub.3CH.sub.2CO.sub.2Cl, and
(CH.sub.3SO.sub.2).sub.2O; Y is chosen from --Si(CH.sub.3).sub.3,
--COCH.sub.3, --CO.sub.2CH.sub.2CH.sub.3, and --SO.sub.2CH.sub.3;
R.sup.1, R.sup.2, and R.sup.3 are each hydrogen; R.sup.4 and
R.sup.5 are each CH.sub.3; and X is bromine.
9. The process of claim 7, wherein the molar/molar ratio of
compound 20 to YX is from about 1:1 to about 1:50, the reaction is
conducted in the presence of an aprotic solvent, and the reaction
is conducted at a temperature ranging from about 0.degree. C. to
about 80.degree. C.
10. The process of claim 7, wherein the yield of compound 21 is
from about 60% to about 90%.
11. A process for the preparation of compound 24s, the process
comprising the following reaction scheme: ##STR00027## wherein:
R.sup.1 and R.sup.2 are independently chosen from hydrogen, OH,
NH.sub.2, SH, CF.sub.3, hydrocarbyl, substituted hydrocarbyl, alkyl
ketal, alkyl thiol ketal, and alkyl dithiol ketal, wherein when
R.sup.1 and R.sup.2 are different they form an epimeric pair, and
wherein R.sup.1 and R.sup.2 together may form a group chosen from
.dbd.O, .dbd.S, cycloalkyl ketal, cycloalkyl thiol ketal, and
cycloalkyl dithiol ketal; R.sup.3 is chosen from hydrogen, halogen,
OH, NH.sub.2, CN, CF.sub.3, SO.sub.2R.sup.8, hydrocarbyl, and
substituted hydrocarbyl; R.sup.6 is chosen from hydrogen, an alkyl
group, an allyl group, a cycloalkylmethyl group, an aryl group, a
benzyl group, and C(O).sub.nR.sup.7; R.sup.7 is chosen from an
alkyl group, an aryl group, and a benzyl group; R.sup.8 is chosen
from hydrocarbyl and substituted hydrocarbyl; X is halogen; and n
is an integer from 1 to 2.
12. The process of claim 11, wherein: R.sup.1, R.sup.2, and R.sup.3
are each hydrogen; R.sup.6 is chosen from hydrogen, CH.sub.3,
--COCH.sub.3, and --CO.sub.2CH.sub.2CH.sub.3; and X is bromine.
13. The process of claim 11, wherein the molar/molar ratio of
compound 23s to demethylating agent is from about 1:5 to about
1:20, the demethylating agent is chosen from BBr.sub.3, BCl.sub.3,
HBr, methionine/MeSO.sub.3H, aluminum bromide, and aluminum
chloride ethanethiol, the reaction is conducted in the presence of
an organic solvent, and the reaction is conducted at a temperature
ranging from about -20.degree. C. to about 120.degree. C.
14. The process of claim 11, wherein the molar/molar ratio of
compound 25s to proton acceptor is from about 1:5 to about 1:100,
the proton acceptor has a pKa of greater that about 8, the reaction
is conducted in the presence of a protic solvent, and the reaction
is conducted at a temperature ranging from about 0.degree. C. to
about 110.degree. C.
15. The process of claim 11, wherein the yield of compound 24s is
from about 60% to about 90%.
16. A process for the preparation of compound 24, the process
comprising the following reaction scheme: ##STR00028## ##STR00029##
wherein: R.sup.1 and R.sup.2 are independently chosen from
hydrogen, OH, NH.sub.2, SH, CF.sub.3, hydrocarbyl, substituted
hydrocarbyl, alkyl ketal, alkyl thiol ketal, and alkyl dithiol
ketal, wherein when R.sup.1 and R.sup.2 are different they form an
epimeric pair, and wherein R.sup.1 and R.sup.2 together may form a
group chosen from .dbd.O, .dbd.S, cycloalkyl ketal, cycloalkyl
thiol ketal, and cycloalkyl dithiol ketal; R.sup.3 is chosen from
hydrogen, halogen, OH, NH.sub.2, CN, CF.sub.3, SO.sub.2R.sup.8,
hydrocarbyl, and substituted hydrocarbyl; R.sup.4 and R.sup.5 are
independently chosen from --(CH.sub.2).sub.nCH.sub.3 and CH.sub.3;
R.sup.8 is chosen from hydrocarbyl and substituted hydrocarbyl; X,
X.sup.1, and X.sup.2 are independently halogen; YX is chosen from
R.sub.mSiX, POX.sub.3, (RCO).sub.2O, RCOX, RSO.sub.2X, and
(RSO.sub.2).sub.2O; m is an integer from 1 to 3; and n is an
integer from 1 to 8.
17. The process of claim 16, wherein: R.sup.1, R.sup.2, and R.sup.3
are each hydrogen; R.sup.4 and R.sup.5 are each CH.sub.3: X is
bromine; and YX is chosen from (CH.sub.3).sub.3SiCl, POCl.sub.3,
(CH.sub.3CO).sub.2O, CH.sub.3COCl, CH.sub.3SO.sub.2Cl,
CH.sub.3CH.sub.2CO.sub.2Cl, and (CH.sub.3SO.sub.2).sub.2O.
18. The process of claim 16, wherein: the molar/molar ratio of
compound 13 to HX is from about 1:2 to about 1:20, the reaction of
compound 13 and HX is conducted in the presence of a protic
solvent, and at a temperature ranging from about 20.degree. C. to
about 100.degree. C.; the molar/molar/molar ratio of compound 14 to
X.sub.2 to proton acceptor is from about 1:0.3:2 to about 1:3:100,
the proton acceptor has a pKa of greater than about 12, the
reaction of compound 14 and X.sub.2 is conducted in the presence of
an organic solvent, and at a temperature ranging from about
-20.degree. C. to about 40.degree. C.; the molar/molar/molar ratio
of compound 16 to X.sub.2 to proton donor is from about 1:0.5:0.5
to about 1:2:10, the reaction of compound 16 and X.sub.2 is
conducted in the presence of a protic solvent or a mixture of a
protic and an organic solvent, and at a temperature ranging from
about 30.degree. C. to about 100.degree. C.; the molar/molar ratio
of compound 19 to proton acceptor is from about 1:1 to about 1:10,
the proton acceptor has a pKa of greater than about 12, the
reaction of compound 19 and the proton acceptor is conducted in the
presence of an aprotic solvent, and at a temperature ranging from
about 20.degree. C. to about 100.degree. C.; the molar/molar ratio
of compound 20 to YX is from about 1:1 to about 1:50, the reaction
is conducted in the presence of an aprotic solvent, at a
temperature ranging from about 0.degree. C. to about 80.degree. C.,
and further comprises hydrolysis in an aqueous solution at a
temperature ranging from about 0.degree. C. to about 100.degree.
C.; the molar/molar ratio of compound 21 to the oxidizing agent is
from about 1:0.5 to about 1:3, the reaction is conducted in the
presence of a protic solvent, and the reaction is conducted at a
temperature ranging from about -5.degree. C. to about 50.degree.
C.; the molar/molar ratio of compound 22 to reducing agent is from
about 10,000:1 to about 100:1, the reaction is conducted in the
presence of a protic solvent, and the reaction is conducted at a
temperature ranging from about 20.degree. C. to about 110.degree.
C.; and the molar/molar/molar ratio of compound 23 to demethylating
agent to proton acceptor is from about 15:5 to about 1:20:100,
contact with the demethylating agent is conducted in the presence
of an organic solvent and at a temperature ranging from about
-20.degree. C. to about 120.degree., and contact with the proton
acceptor, which has a pKa of greater than about 8, is conducted in
the presence of a protic solvent and at a temperature ranging from
about 0.degree. C. to about 110.degree. C.
19. The process of claim 16, wherein: the optical activity of
compounds 13 and 14 is (+) or (-), and the configuration of C-13
and C-9, respectively, is chosen from RR, RS, SR, and SS, provided
that the C-15 and the C-16 carbons are both either on the alpha
face or the beta face of the molecule; the optical activity of
compounds 16, 19, 20, and 21 is (+) or (-), and the configuration
of C-5, C-13, and C-9, respectively, is chosen from RRR, RRS, RSR,
RSS, SRR, SRS, SSR, and SSS, provided that the C-15 and the C-16
carbons are both either on the alpha face or the beta face of the
molecule; and the optical activity of compounds 22, 23, and 24 is
(+) or (-), and the configuration of C-5, C-13, C-14, and C-9,
respectively, is chosen from RRRR, RRSR, RRRS, RRSS, RSRR, RSSR,
RSRS, RSSS, SRRR, SRSR, SRRS, SRSS, SSRR, SSSR, SSRS, and SSSS,
provided that the C-15 and the C-16 carbons are both either on the
alpha face or the beta face of the molecule.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority from Provisional
Application Ser. No. 61/056,079 filed on May 27, 2008, which is
hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention generally relates to processes and
intermediate compounds useful for the production of normorphinans
and derivatives of normorphinans.
BACKGROUND OF THE INVENTION
[0003] Noroxymophone is a common starting material to make a series
of semi-synthetic opiate N-substituted derivatives (i.e., "nal"
compounds) such as naltrexone and naloxone. Noroxymorphone is
currently produced in a multi-step process from a poppy derived
opiate. As demand of these semi-synthetic opiate derivatives has
increased, there is a need for noroxymorphone to be produced more
efficiently and at higher purity.
SUMMARY OF THE INVENTION
[0004] The present invention provides processes and compounds for
the preparation of normorphinan compounds. Among the various
aspects of the invention is a provision for compound comprising
Formula 21a:
##STR00001##
[0005] wherein: [0006] R.sup.1 and R.sup.2 are independently chosen
from hydrogen, OH, NH.sub.2, SH, CF.sub.3, hydrocarbyl, substituted
hydrocarbyl, alkyl ketal, alkyl thiol ketal, and alkyl dithiol
ketal, wherein when R.sup.1 and R.sup.2 are different they form an
epimeric pair, and wherein R.sup.1 and R.sup.2 together may form a
group chosen from .dbd.O, .dbd.S, cycloalkyl ketal, cycloalkyl
thiol ketal, and cycloalkyl dithiol ketal; [0007] R.sup.3 is chosen
from hydrogen, halogen, OH, NH.sub.2, CN, CF.sub.3,
SO.sub.2R.sup.8, hydrocarbyl, and substituted hydrocarbyl; [0008]
R.sup.4 and R.sup.5 are independently chosen from
--(CH.sub.2).sub.nCH.sub.3 and CH.sub.3; [0009] R.sup.8 is chosen
from hydrocarbyl and substituted hydrocarbyl; [0010] X is halogen;
and [0011] Y is chosen from an aryl group, a benzyl group, an acyl
group, a formyl ester, an alkoxycarbonyl group, a benzyloxycarbonyl
group, an alkylamidocarbonyl group, a trialkylsilyl group, an
alkylsulfonyl group, and an aryl sulfonyl group; and [0012] n is an
integer from 1 to 8.
[0013] Another aspect of the invention encompasses compound
comprising Formula 25:
##STR00002##
[0014] wherein: [0015] R.sup.1 and R.sup.2 are independently chosen
from hydrogen, OH, NH.sub.2, SH, CF.sub.3, hydrocarbyl, substituted
hydrocarbyl, alkyl ketal, alkyl thiol ketal, and alkyl dithiol
ketal, wherein when R.sup.1 and R.sup.2 are different they form an
epimeric pair) and wherein R.sup.1 and R.sup.2 together may form a
group chosen from .dbd.O, .dbd.S, cycloalkyl ketal, cycloalkyl
thiol ketal, and cycloalkyl dithiol ketal; [0016] R.sup.3 is chosen
from hydrogen, halogen, OH, NH.sub.2, CN, CF.sub.3,
SO.sub.2R.sup.8, hydrocarbyl, and substituted hydrocarbyl; [0017]
R.sup.6 is chosen from hydrogen, an alkyl group, an allyl group, a
cycloalkylmethyl group, an aryl group, a benzyl group, and
C(O).sub.nR.sup.7; [0018] R.sup.7 is chosen from an alkyl group, an
aryl group, and a benzyl group; [0019] R.sup.8 is chosen from
hydrocarbyl and substituted hydrocarbyl; [0020] X is halogen; and
[0021] n is an integer from 1 to 2.
[0022] Still another aspect provides a process for the preparation
of compound 21, the process comprising the following reaction
scheme:
##STR00003##
[0023] wherein: [0024] R.sup.1 and R.sup.2 are independently chosen
from hydrogen, OH, NH.sub.2, SH, CF.sub.3, hydrocarbyl, substituted
hydrocarbyl, alkyl ketal, alkyl thiol ketal, and alkyl dithiol
ketal, wherein when R.sup.1 and R.sup.2 are different they form an
epimeric pair, and wherein R.sup.1 and R.sup.2 together may form a
group chosen from .dbd.O, .dbd.S, cycloalkyl ketal, cycloalkyl
thiol ketal, and cycloalkyl dithiol ketal; [0025] R.sup.3 is chosen
from hydrogen, halogen, OH, NH.sub.2, CN, CF.sub.3,
SO.sub.2R.sup.8, hydrocarbyl, and substituted hydrocarbyl; [0026]
R.sup.4 and R.sup.5 are independently chosen from
--(CH.sub.2).sub.nCH.sub.3, and CH.sub.3; [0027] R.sup.8 is chosen
from hydrocarbyl and substituted hydrocarbyl; [0028] X is halogen;
[0029] Y is chosen from an aryl group, a benzyl group, an acyl
group, a formyl ester, an alkoxycarbonyl group, a benzyloxycarbonyl
group, an alkylamidocarbonyl group, a trialkylsilyl group, an
alkylsulfonyl group, and an aryl sulfonyl group; and [0030] YX is
chosen from R.sub.mSiX, POX.sub.3, (RCO).sub.2O, RCOX, RSO.sub.2X,
and (RSO.sub.2).sub.2O; [0031] m is an integer from 1 to 3; and
[0032] n is an integer from 1 to 8.
[0033] A further aspect of the invention encompasses a process for
the preparation of compound 24s, the process comprising the
following reaction scheme:
##STR00004##
[0034] wherein: [0035] R.sup.1 and R.sup.2 are independently chosen
from hydrogen, OH, NH.sub.2, SH, CF.sub.3, hydrocarbyl, substituted
hydrocarbyl alkyl ketal, alkyl thiol ketal, and alkyl dithiol
ketal, wherein when R.sup.1 and R.sup.2 are different they form an
epimeric pair, and wherein R.sup.1 and R.sup.2 together may form a
group chosen from .dbd.O, .dbd.S, cycloalkyl ketal, cycloalkyl
thiol ketal, and cycloalkyl dithiol ketal; [0036] R.sup.3 is chosen
from hydrogen, halogen, OH, NH.sub.2, CN, CF.sub.3,
SO.sub.2R.sup.8, hydrocarbyl, and substituted hydrocarbyl; [0037]
R.sup.6is chosen from hydrogen, an alkyl group, an allyl group, a
cycloalkylmethyl group, an aryl group, a benzyl group, and
C(O).sub.nR.sup.7; [0038] R.sup.7 is chosen from an alkyl group, an
aryl group, and a benzyl group; [0039] R.sup.8 is chosen from
hydrocarbyl and substituted hydrocarbyl; [0040] X is halogen; and
[0041] n is an integer from 1 to 2.
[0042] Yet another aspect of the invention provides a process for
the preparation of compound 24, the process comprising the
following reaction scheme:
##STR00005## ##STR00006##
[0043] wherein: [0044] R.sup.1 and R.sup.2 are independently chosen
from hydrogen, OH, NH.sub.2, SH, CF.sub.3, hydrocarbyl, substituted
hydrocarbyl, alkyl ketal, alkyl thiol ketal, and alkyl dithiol
ketal, wherein when R.sup.1 and R.sup.2 are different they form an
epimeric pair, and wherein R.sup.1 and R.sup.2 together may form a
group chosen from .dbd.O, .dbd.S, cycloalkyl ketal, cycloalkyl
thiol ketal, and cycloalkyl dithiol ketal; [0045] R.sup.3 is chosen
from hydrogen, halogen, OH, NH.sub.2, CN, CF.sub.3,
SO.sub.2R.sup.8, hydrocarbyl, and substituted hydrocarbyl; [0046]
R.sup.4 and R.sup.5 are independently chosen from
--(CH.sub.2).sub.nCH.sub.3 and CH.sub.3; [0047] R.sup.8 is chosen
from hydrocarbyl and substituted hydrocarbyl; [0048] X, X.sup.1,
and X.sup.2 are independently halogen; [0049] YX is chosen from
R.sub.mSiX, POX.sub.3, (RCO).sub.2O, RCOX, RSO.sub.2X, and
(RSO.sub.2).sub.2O; [0050] m is an integer from 1 to 3; and [0051]
n is an integer from 1 to 8.
[0052] Other aspects and features of the invention are described in
more detail below.
DETAILED DESCRIPTION
[0053] Processes and compounds for preparing normorphinan
compounds, derivatives, and analogs thereof have been discovered.
In particular, the compounds and processes may be used for
preparing noroxymorphone, noroxymorphone analogs, and
noroxymorphone derivatives. The processes of the invention are more
efficient, have higher yields, and produce fewer undesirable
side-products than currently used synthetic routes.
(I) Normorphinan Compounds
[0054] One aspect of the invention encompasses compounds that may
be used as intermediates in the preparation of normorphinan related
compounds. For purposes of discussion, the ring atoms of a
morphinan compound are numbered as
##STR00007##
diagrammed below. The core morphinan compound may have four chiral
carbons; namely, C-5, C-13, C-14, and C-9.
[0055] In one embodiment of the invention, the normorphinan
compound
##STR00008##
comprises Formula 21a:
[0056] wherein: [0057] R.sup.1 and R.sup.2 are independently
selected from the group consisting of hydrogen, OH, NH.sub.2, SH,
CF.sub.3, hydrocarbyl, substituted hydrocarbyl, alkyl ketal, alkyl
thiol ketal, and alkyl dithiol ketal, wherein when R.sup.1 and
R.sup.2 are different they form an epimeric pair, and wherein
R.sup.1 and R.sup.2 together may form a group selected from the
group consisting of .dbd.O, .dbd.S, cycloalkyl ketal, cycloalkyl
thiol ketal, and cycloalkyl dithiol ketal; [0058] R.sup.3 is
selected from the group consisting of hydrogen, halogen, OH,
NH.sub.2, CN, CF.sub.3, SO.sub.2R.sup.8, hydrocarbyl, and
substituted hydrocarbyl; [0059] R.sup.4 and R.sup.5 are
independently selected from the group consisting of
--(CH.sub.2).sub.nCH.sub.3 and CH.sub.3; [0060] R.sup.8 is selected
from the group consisting hydrocarbyl and substituted hydrocarbyl;
[0061] X is halogen; [0062] Y is selected from the group consisting
of an aryl group, a benzyl group, an acyl group, a formyl ester, an
alkoxycarbonyl group, a benzyloxycarbonyl group, an
alkylamidocarbonyl group, a trialkylsilyl group, an alkylsulfonyl
group, and an aryl sulfonyl group; and [0063] n is an integer from
1 to 8.
[0064] The optical activity, with respect to the rotation of
polarized light, of the compound comprising Formula 21a may be (+)
or (-). Furthermore, the configuration of the chiral carbons, C-5,
C-13, and C-9, respectively, of the compound may be RRR, RRS, RSR,
RSS, SRR, SRS, SSR, or SSS, provided that the C-15 and the C-16
carbons are both either on the alpha face or the beta face of the
molecule.
[0065] In a preferred iteration of this embodiment, R.sup.1,
R.sup.2, and R.sup.3 are each hydrogen; R.sup.4 and R.sup.5 are
each CH.sub.3; X is bromine; and Y is selected from the group
consisting of --Si(CH.sub.3).sub.3, --COCH.sub.3,
--CO.sub.2CH.sub.2CH.sub.3, and --SO.sub.2CH.sub.3. Table A
presents exemplary compounds comprising Formula 21a.
TABLE-US-00001 TABLE A Exemplary Compounds Comprising Formula 21a.
Compound Number Structure A-1 ##STR00009## A-2 ##STR00010## A-3
##STR00011## A-4 ##STR00012##
##STR00013##
[0066] In another embodiment, the normorphinan compound comprises
Formula 25:
[0067] wherein: [0068] R.sup.1 and R.sup.2 are independently
selected from the group consisting of hydrogen, OH, NH.sub.2, SH,
CF.sub.3, hydrocarbyl, substituted hydrocarbyl, alkyl ketal, alkyl
thiol ketal, and alkyl dithiol ketal, wherein when R.sup.1 and
R.sup.2 are different they form an epimeric pair, and wherein
R.sup.1 and R.sup.2 together may form a group selected from the
group consisting of .dbd.O, .dbd.S, cycloalkyl ketal, cycloalkyl
thiol ketal, and cycloalkyl dithiol ketal; [0069] R.sup.3 is
selected from the group consisting of hydrogen, halogen, OH,
NH.sub.2, CN, CF.sub.3, SO.sub.2R.sup.8, hydrocarbyl, and
substituted hydrocarbyl; [0070] R.sup.3 is selected from the group
consisting of hydrogen, an alkyl group, an allyl group, a
cycloalkylmethyl group, an aryl group, a benzyl group, and
C(O).sub.nR.sup.7; [0071] R.sup.7 is selected from the group
consisting of an alkyl group, an aryl group, and a benzyl group;
[0072] R.sup.8 is selected from the group consisting hydrocarbyl
and substituted hydrocarbyl; [0073] X is halogen; and [0074] n is
an integer from 1 to 2.
[0075] The optical activity of the compound comprising Formula 25
may be (+) or (-), and the configuration of the chiral carbons,
C-5, C-13, C-14, and C-9, respectively, of the compound may be
RRRR, RRSR, RRRS, RRSS, RSRR, RSSR, RSRS, RSSS, SRRR, SRSR, SRRS,
SRSS, SSRR, SSSR, SSRS, or SSSS, provided that the C-15 and the
C-16 carbons are both either on the alpha face or the beta face of
the molecule.
[0076] In a preferred iteration of this embodiment, R.sup.1,
R.sup.2, and R.sup.3 are each hydrogen; R.sup.6 is selected from
the group consisting of hydrogen, methyl, --COCH.sub.3, and
--CO.sub.2CH.sub.2CH.sub.3, and X is bromine. Exemplary compounds
comprising Formula 25 are presented in Table B.
TABLE-US-00002 TABLE B Exemplary Compounds Comprising Formula 25.
Compound Number Structure B-1 ##STR00014## B-2 ##STR00015## B-3
##STR00016## B-4 ##STR00017##
(II) Process for Preparing Compound 24.
[0077] Another aspect of the invention provides a process for
preparing normorphinans, normorphinan analogs, and derivatives
thereof. For the purposes of illustration, Reaction Scheme 1
depicts the preparation of the normorphinan compound comprising
Formula 24 according to one aspect of the invention:
##STR00018## ##STR00019##
[0078] wherein: [0079] R.sup.1 and R.sup.2 are independently
selected from the group consisting of hydrogen, OH, NH.sub.2, SH,
CF.sub.3, hydrocarbyl, substituted hydrocarbyl, alkyl ketal, alkyl
thiol ketal, and alkyl dithiol ketal, wherein when R.sup.1 and
R.sup.2 are different they form an epimeric pair, and wherein
R.sup.1 and R.sup.2 together may form a group selected from the
group consisting of .dbd.O, .dbd.S, cycloalkyl ketal, cycloalkyl
thiol ketal, and cycloalkyl dithiol ketal; [0080] R.sup.3 is
selected from the group consisting of hydrogen, halogen, OH,
NH.sub.2, CN, CF.sub.3, SO.sub.2R.sup.8, hydrocarbyl, and
substituted hydrocarbyl; [0081] R.sup.4 and R.sup.5 are
independently selected from the group consisting of
(CH.sub.2).sub.nCH.sub.3 and CH.sub.3; [0082] R.sup.8 is selected
from the group consisting hydrocarbyl and substituted hydrocarbyl;
[0083] X, X.sup.1, and X.sup.2 are independently halogen; [0084] YX
is selected from the group consisting of R.sub.mSiX, POX.sub.3,
(RCO).sub.2O, RCOX, RSO.sub.2X, and (RSO.sub.2).sub.2O; [0085] m is
an integer from 1 to 3; and [0086] n is an integer from 1 to 8.
[0087] In a preferred iteration, the constituents of the reaction
comprise: [0088] R.sup.1, R.sup.2, and R.sup.3 are each hydrogen;
[0089] R.sup.4 and R.sup.5 are each CH.sub.3; [0090] X is bromine;
and [0091] YX is selected from the group consisting of
(CH.sub.3).sub.3SiCl, POCl.sub.3, (CH.sub.3CO).sub.2O,
CH.sub.3COCl, CH.sub.3SO.sub.2Cl, CH.sub.3CH.sub.2CO.sub.2Cl, and
(CH.sub.3SO.sub.2).sub.2O.
[0092] Reaction Scheme 1 comprises eight steps (A-H), each of which
is detailed below.
(a) Step A: Conversion of Compound 13 to Compound 14
[0093] In Step A of Reaction Scheme 1, compound 13 is contacted
with HX to form compound 14. In general, HX is an acid. Suitable
acids include hydrobromic acid, hydrochloric acid, hydroiodic acid,
sulfuric acid, methanesulfonic acid, trifluoracetic acid,
p-toluenesulfonic acid. In an exemplary embodiment, HX may be
hydrobromic acid. The amount of HX contacted with compound 13 can
and will vary. Typically, the molar/molar ratio of compound 13 to
HX may range from about 1:2 to about 1:20. In a preferred
embodiment, the molar/molar ratio of compound 13 to HX may range
from about 1:2.5 to about 1:10. In a more preferred embodiment,
molar/molar ratio of compound 13 to HX may range from about 1:3 to
about 1:5. Contact between compound 13 and HX may proceed slowly
over a period of time. For example, in one embodiment, HX may be
introduced dropwise over a period of time of at least one hour.
[0094] The reaction is generally conducted in the presence of a
protic solvent. Non-limiting examples of suitable protic solvents
include methanol, ethanol, isopropanol, n-propanol, isobutanol,
t-butanol, n-butanol, formic acid, acetic acid, water, and
combinations thereof. In an exemplary embodiment, the solvent used
in the reaction may be methanol. In general, the weight/weight
ratio of solvent to compound 13 may range from about 1:1 to about
100:1. In a preferred embodiment, the weight/weight ratio of
solvent to compound 13 may range from about 2:1 to about 25:1. In a
more preferred embodiment, the weight/weight ratio of solvent to
compound 13 may range from about 5:1 to about 10:1.
[0095] In general, the reaction may be conducted at a temperature
that ranges from about 20.degree. C. to about 100.degree. C. In a
preferred embodiment, the temperature of the reaction may range
from about 50.degree. C. to about 90.degree. C. In a more preferred
embodiment, the temperature of the reaction may range from about
70.degree. C. to about 85.degree. C. The reaction is preferably
performed under ambient pressure, and preferably in an inert
atmosphere (e.g., nitrogen or argon).
[0096] Typically, the reaction is allowed to proceed for a
sufficient period of time until the reaction is complete, as
determined by chromatography (e.g., HPLC). In this context, a
"completed reaction" generally means that the reaction mixture
contains a significantly diminished amount of compound 13 and a
significantly increased amount of compound 14 compared to the
amounts of each present at the beginning of the reaction.
Typically, the amount of compound 13 remaining in the mixture may
be less than about 5%.
[0097] The yield of compound 14 may vary. Typically, the yield of
compound 14 may be range from about 60% to about 90%. In one
embodiment, the yield of compound 14 may range from about 60% to
about 70%. In another embodiment, the yield of compound 14 may
range from about 70% to about 80%. In still another embodiment, the
yield of compound 14 may range from about 80% to about 90%.
(b) Step B: Conversion of Compound 14 to Compound 16
[0098] In Step B of Reaction Scheme 1, compound 14 is contacted
with X.sub.2 and then contacted with a proton acceptor to form
compound 16. X.sub.2 may be bromine, chlorine, or iodine. In a
preferred embodiment, X.sub.2 may be bromine (Br.sub.2). In one
embodiment, the molar/molar ratio of compound 14 to X.sub.2 may
range from about 1:0.3 to about 1:3. In another embodiment, the
molar/molar ratio of compound 14 to X.sub.2 may range from about
1:0.5 to about 1:2. In a preferred embodiment, molar/molar ratio of
compound 14 to X.sub.2 may range from about 1:1 to about 1:1.1.
Contact between compound 14 and X.sub.2 may proceed slowly over a
period of time. In one embodiment, for example, X.sub.2 may be
introduced dropwise over a period of time of at least 30 minutes.
The reaction is generally performed under ambient pressure
[0099] Compound 14 may be contacted with X.sub.2 in the presence of
an organic solvent or, more preferably, a mixture of an organic
solvent and an acid. Non-limiting examples of suitable organic
solvents include benzene, butyl acetate, t-butyl methylether,
t-butyl methylketone, chlorobenzene, chloroform, cyclohexane,
dichloromethane, dichloroethane, diethyl ether, ethyl acetate,
fluorobenzene, heptane, hexane, isopropyl acetate,
methyltetrahydrofuran, pentyl acetate, n-propyl acetate,
tetrahydrofuran, toluene, and combinations thereof. In a preferred
embodiment, the solvent may be chloroform. In an especially
preferred embodiment, chloroform may be mixed with an acid, such as
acetic acid or propanoic acid. The concentration of the acid in the
chloroform may be about 5%, about 10%, about 20%, about 30%, about
40%, about 50%, about 60%, about 70%, about 80% to about 90%. In an
exemplary embodiment, the concentration of the acid in the
chloroform may be about 50%.
[0100] In one embodiment, the weight/weight ratio of solvent to
compound 14 may range from about 2:1 to about 100:1. In another
embodiment, the weight/weight ratio of solvent to compound 14 may
range from about 5:1 to about 80:1. In still another embodiment,
the weight/weight ratio of solvent to compound 14 may range from
about 10:1 to about 60:1. In a preferred embodiment, the
weighVweight ratio of solvent to compound 14 may range from about
35:1 to about 50:1.
[0101] The reaction further comprises contact with a proton
acceptor. Typically, the proton acceptor will have a pKa of greater
than about 12. Non-limiting examples of suitable proton acceptors
having this characteristic include hydroxides of alkali metals and
alkaline earth metals (such as, for example, NaOH, KOH, and
Ca(OH).sub.2 and the like), group 1 salts of carbanions, amides,
and hydrides (such as, for example, butyl lithium, sodium amide
(NaNH.sub.2), sodium hydride (NaH), and the like), alkoxides of
alkali metals (such as, for example, potassium butoxide, sodium
methoxide, and the like), and a buffer that has a pH greater than
about 10 (such as, for example, Na.sub.3PO.sub.4 or
K.sub.3PO.sub.4). In a preferred embodiment, the proton acceptor
may be NaOH, KOH, LiOH, Ca(OH).sub.2, or NaH. In an exemplary
embodiment, the proton acceptor may be NaOH.
[0102] The molar/molar ratio of compound 14 to proton acceptor may
range from about 1:2 to about 1:100. In one embodiment, the
molar/molar ratio of compound 14 to proton acceptor may range from
about 1:2.5 to about 1:40. In another embodiment, the molar/molar
ratio of compound 14 to proton acceptor may range from about 1:3 to
about 1:15. In a preferred embodiment, the molar/molar ratio of
compound 14 to proton acceptor may range from about 1:3 to about
1:5. Stated another way, the final pH of the reaction mixture may
be greater than about pH 10, preferably greater than about pH 12,
and more preferably greater than about pH 13. Contact between the
reaction mixture and the proton acceptor may occur slowly. In one
embodiment, the proton acceptor may be introduced dropwise into the
reaction mixture over a period of time. In a preferred embodiment,
the reaction mixture may be introduced dropwise into the proton
acceptor over a period of time of at least one hour.
[0103] The reaction may be performed at a temperature that ranges
from about -20.degree. C. to about 40.degree. C. In a preferred
embodiment, the reaction may occur at a temperature that ranges
from about -1.degree. C. to about 10.degree. C. The reaction is
typically performed under ambient pressure.
[0104] The reaction is generally allowed to proceed for a
sufficient period of time until the reaction is complete, as
determined by chromatography (e.g., HPLC). Typically, the amount of
compound 14 remaining in the mixture may be less than about 5%.
[0105] The yield of compound 16 may range from about 60% to about
90%. In one embodiment, the yield of compound 16 may range from
about 60% to about 70%. In another embodiment, the yield of
compound 16 may range from about 70% to about 80%. In still another
embodiment, the yield of compound 16 may range from about 80% to
about 90%.
(c) Step C: Conversion of Compound 16 to Compound 19
[0106] Step C of Reaction Scheme 1 comprises contacting compound 16
with X.sub.2 and a proton donor to form compound 19. X.sub.2 is as
defined above in (II)(b). In general, the molar/molar ratio of
compound 16 to X.sub.2 may range from about 1:0.5 to about 1:2. In
a preferred embodiment, the molar/molar ratio of compound 16 to
X.sub.2 may range from about 1:0.9 to about 1:1.1. Typically,
contact between compound 16 and X.sub.2 will proceed slowly over a
period of time. In one embodiment, for example, X.sub.2 may be
introduced dropwise over a period of time of at least 30
minutes.
[0107] Non-limiting examples of suitable proton donors include
H.sub.2SO.sub.4, HCl, HBr, HI, H.sub.3PO.sub.4, CF.sub.3SO.sub.3H,
MeSO.sub.3H, p-toluenesulfonic acid, HClO.sub.3, HBrO.sub.4,
HIO.sub.3, and HIO.sub.4. In a preferred embodiment, the proton
donor may be MeSO.sub.3H or H.sub.2SO.sub.4. In one embodiment, the
molar/molar ratio of compound 16 to proton donor may range from
about 1:0.5 to about 1:10. In another embodiment the molar/molar
ratio of compound 16 to proton donor may range from about 1:0.8 to
about 1:5. In a preferred embodiment, the molar/molar ratio of
compound 16 to proton donor may range from about 1:1 to about
1:2.
[0108] Compound 16 is typically contacted with X.sub.2 and the
proton donor in the presence of a protic solvent or, more
preferably, a mixture of a protic and an organic solvent. Suitable
protic solvents are presented above in section (II)(a), and
suitable organic solvents are presented above in (II)(b). Preferred
solvent systems include a mixture of methanol and
trimethylorthoformate, a mixture of ethanol and
triethylorthoformate, or a mixture of n-propanol and
tripropylorthoformate. In an exemplary embodiment, the solvent
system may be a mixture of methanol and trimethylorthoformate. In
one embodiment, the weight/weight ratio of solvent to compound 16
may range from about 2:1 to about 100:1. In another embodiment, the
weight/weight ratio of solvent to compound 16 may range from about
3:1 to about 30:1. In a preferred embodiment, the weight/weight
ratio of solvent to compound 16 may range from about 5:1 to about
10:1.
[0109] The reaction may be conducted at a temperature that ranges
from about 30.degree. C. to about 100.degree. C. Preferably, the
reaction may be conducted at a temperature that ranges from about
40.degree. C. to about 70.degree. C. The reaction is preferably
performed under ambient pressure, but optionally may be carried out
under reduced pressure.
[0110] Typically, the reaction is allowed to proceed for a
sufficient period of time until the reaction is complete, as
determined by chromatography (e.g., HPLC), and the amount of
compound 16 remaining in the mixture may be less than about 5%.
[0111] The yield of compound 19 may range from about 60% to about
90%. In one embodiment, the yield of compound 19 may range from
about 60% to about 70%. In another embodiment, the yield of
compound 19 may range from about 70% to about 80%. In still another
embodiment, the yield of compound 19 may range from about 80% to
about 90%.
(d) Step D: Conversion of Compound 19 to Compound 20
[0112] In Step D of Reaction Scheme 1, compound 19 is contacted
with a proton acceptor to form compound 20. Typically, the proton
acceptor will have a pKa of greater than about 12. Examples of
suitable proton acceptors having this characteristic are presented
in (II)(b). Preferred proton donors include butyl lithium,
potassium tert-butoxide, sodium tert-butoxide, sodium hydride,
sodium amide, and (Me.sub.3Si).sub.2NLi. In an exemplary
embodiment, the proton acceptor may be potassium tert-butoxide or
sodium tert-butoxide. The molar/molar ratio of compound 19 to
proton acceptor can and will vary. In one embodiment, molar/molar
ratio of compound 19 to proton acceptor may range from about 1:1 to
about 1:10. In another embodiment, molar/molar ratio of compound 19
to proton acceptor may range from about 1:2 to about 1:8. In a
preferred embodiment, molar/molar ratio of compound 19 to proton
acceptor may range from about 1:4 to about 1:6.
[0113] The reaction may be conducted in the presence of an aprotic
solvent. Non-limiting examples of aprotic solvents include ether
solvents, acetonitrile, benzene, N,N-dimethylformamide, dimethyl
sulfoxide, N,N-dimethylpropionamide,
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone,
1,3-dimethyl-2-imidazolidinone, 1,2-dimethoxyethane,
bis(2-methoxyethyl)ether, N,N-dimethylacetamide,
N-methylpyrrolidinone, ethyl acetate, ethyl formate, formamide,
hexamethylphosphoramide, methyl acetate, N-methylacetamide,
N-methylformamide, methylene chloride, nitrobenzene, nitromethane,
propionitrile, sulfolane, tetramethylurea, tetrahydrofuran,
2-methyl tetrahydrofuran, toluene, trichloromethane, and
combinations thereof. In a preferred embodiment, the aprotic
solvent may be tetrahydrofuran (THF). In one embodiment, the
weight/weight ratio of solvent to compound 19 may range from about
2:1 to about 100:1. In another embodiment, the weight/weight ratio
of solvent to compound 19 may range from about 2.5:1 to about 20:1.
In a preferred embodiment, the weight/weight ratio of solvent to
compound 19 may range from about 3:1 to about 8:1.
[0114] In one embodiment, the reaction may be conducted at a
temperature that ranges from about 20.degree. C. to about
100.degree. C. In another embodiment, the reaction may be conducted
at a temperature that ranges from about 40.degree. C. to about
80.degree. C. In a preferred embodiment, the temperature of the
reaction may range from about 50.degree. C. to about 70.degree. C.
The reaction is preferably performed under ambient pressure, and
preferably in an inert atmosphere (e.g., nitrogen or argon).
[0115] The reaction is generally allowed to proceed for a
sufficient period of time until the reaction is complete, as
determined by chromatography (e.g., HPLC). Typically, the amount of
compound 19 remaining in the mixture may be less than about 5%.
[0116] The yield of compound 20 may range from about 60% to about
90%. In one embodiment, the yield of compound 20 may range from
about 60% to about 70%. In another embodiment, the yield of
compound 20 may range from about 70% to about 80%. In still another
embodiment, the yield of compound 20 may range from about 80% to
about 90%.
(e) Step E: Conversion of Compound 20 to Compound 21
[0117] Step E of Reaction Scheme 1 comprises contacting compound 20
with reagent YX. Reagent YX is as defined above. In a preferred
embodiment, YX may be (CH.sub.3).sub.3SiCl, CH.sub.3COCl,
CH.sub.3SO.sub.2Cl, or CH.sub.3CH.sub.2CO.sub.2Cl, The molar/molar
ratio of compound 20 to YX may vary. In one embodiment, the
molar/molar ratio of compound 20 to YX may range from about 1:1 to
about 1:50. In another embodiment, the molar/molar ratio of
compound 20 to YX may range from about 1:1.2 to about 1:15. In a
preferred embodiment, the molar/molar ratio of compound 20 to YX
may range from about 1:1.5 to about 1:5.
[0118] The reaction may be conducted in the presence of an aprotic
solvent. Examples of suitable aprotic solvents are presented above
in (II)(d). In a preferred embodiment, the aprotic solvent may be
acetonitrile. In one embodiment, the weight/weight ratio of solvent
to compound 20 may range about 2:1 to about 50:1. In another
embodiment, the weight/weight ratio of solvent to compound 20 may
range about 3:1 to about 40:1. In a preferred embodiment, the
weigh/weight ratio of solvent to compound 20 may range from about
5:1 to about 20:1. Contact between compound 20 and reagent YX may
be preformed at a temperature that ranges from about 0.degree. C.
to about 80.degree. C. Preferably, contact between compound 20 and
reagent YX may be preformed at a temperature that ranges from about
15.degree. C. to about 35.degree. C. The reaction is preferably
performed under ambient pressure.
[0119] The reaction further comprises hydrolysis in the presence of
an aqueous solution to form compound 21. In a preferred embodiment,
the aqueous solution may be water or a solution of ammonium
hydroxide. In general, the pH of the aqueous solution may range
from about pH 7 to about pH 12, or more preferably from about pH 8
to about pH 10. The weight/weight ratio of compound 20 to aqueous
solution may range from 1:1 to about 1:50, or more preferably from
about 1:2 to about 1:8. The hydrolysis may be conducted at a
temperature that ranges from about 0.degree. C. to about
100.degree. C., or more preferably from about 10.degree. C. to
about 50.degree. C. The reaction is preferably performed under
ambient pressure.
[0120] The reaction generally is allowed to proceed for a
sufficient period of time until the reaction is complete, as
determined by chromatography (e.g., HPLC). Typically, the amount of
compound 20 remaining in the mixture may be less than about 5%.
[0121] The yield of compound 21 may range from about 60% to about
90%. In one embodiment, the yield of compound 21 may range from
about 60% to about 70%. In another embodiment, the yield of
compound 21 may range from about 70% to about 80%. In still another
embodiment, the yield of compound 21 may range from about 80% to
about 90%.
(f) Step F: Conversion of Compound 21 to Compound 22
[0122] In Step F of Reaction Scheme 1, compound 21 is contacted
with an oxidizing agent to form compound 22. The oxidizing agent
may be selected from the group consisting of R.sup.zCO.sub.3H,
R.sup.zCO.sub.2H/H.sub.2O.sub.2, and R.sup.zCO.sub.2H/other
oxidant, wherein R.sup.z is selected from the group consisting of
alkyl, substituted alkyl, aryl, and substituted aryl. In a
preferred embodiment the oxidizing agent may be a peroxy acid, such
as peracetic acid or 3-chloroperoxybenzoic acid. In one embodiment,
the molar/molar ratio of compound 21 to oxidizing agent may range
from about 1:0.5 to about 1:3. In another embodiment, the
molar/molar ratio of compound 21 to oxidizing agent may range from
about 1:0.8 to about 1:2. In a preferred embodiment, the
molar/molar ratio of compound 21 to oxidizing agent may range from
about 1:1 to about 1:1.2.
[0123] The reaction may be conducted in the presence of a protic
solvent. Suitable protic solvents are presented above in (II)(a).
In a preferred embodiment, the protic solvent may be a combination
of water and acetic acid. The solvent system may alternatively, or
additionally, comprise other protic solvents such as alcohol or
other water-miscible solvent; thus, for example, the protic solvent
may be water, a water/alcohol mixture, or a water/water-miscible
solvent mixture. Representative alcohols for the water/alcohol
mixture include, for example, methanol, ethanol, t-butyl alcohol,
n-propyl alcohol, n-butyl alcohol, and combinations thereof. Other
water-miscible solvents for the water/water-miscible solvent
mixture include, for example, acetonitrile, N,N-dimethylformamide,
1-methyl-2-pyrrolidinone, N,N-dimethylacetamide, and combinations
thereof. The weight/weight ratio of solvent to compound 21 may
range from about 2:1 to about 50:1. Preferably, the weight/weight
ratio of solvent to compound 21 range from about 2:1 to about
5:1.
[0124] The reaction may be conducted at a temperature that ranges
from about -5.degree. C. to about 50.degree. C. In a preferred
embodiment, the temperature of the reaction may range from about
5.degree. C. to about 35.degree. C. The reaction is preferably
performed under ambient pressure.
[0125] The reaction generally is allowed to proceed for a
sufficient period of time until the reaction is complete, as
determined by chromatography (e.g., HPLC). Typically, the amount of
compound 21 remaining in the mixture may be less than about 5%.
[0126] The yield of compound 22 may range from about 60% to about
90%. In one embodiment, the yield of compound 22 may range from
about 60% to about 70%. In another embodiment, the yield of
compound 22 may range from about 70% to about 80%. In still another
embodiment, the yield of compound 22 may range from about 80% to
about 90%.
(g) Step G: Conversion of Compound 22 to Compound 23
[0127] Step G of Reaction Scheme 1 comprises the reduction of
compound 22 to form compound 23. For this, compound 22 is contacted
with a reducing agent. A variety of reducing approaches may be
employed including, for example, chemical reduction, catalytic
reduction, and the like. Representative reducing agents for use in
catalytic reduction methods with hydrogen include commonly used
catalysts such as, for example, platinum catalysts (e.g., platinum
black, colloidal platinum, platinum oxide, platinum plate, platinum
sponge, platinum wire, and the like), palladium catalysts (e.g.,
palladium black, palladium on barium carbonate, palladium on barium
sulfate, colloidal palladium, palladium on carbon, palladium
hydroxide on carbon, palladium oxide, palladium sponge, and the
like), nickel catalysts (e.g., nickel oxide, Raney nickel, reduced
nickel, and the like), cobalt catalysts (e.g., Raney cobalt,
reduced cobalt, and the like), iron catalysts (e.g., Raney iron,
reduced iron, Ullmann iron, and the like), and others. In a
preferred embodiment, compound 22 is reduced catalytically by
palladium on carbon (Pd--C) under pressurized hydrogen. The
molar/molar ratio of compound 22 to reducing agent may range from
about 10,000:1 to about 100:1, or more preferably from about 5000:1
to about 1000:1.
[0128] The reaction may be conducted in the presence of a protic
solvent, such as, for example, a combination of water and acetic
acid. Other suitable protic or water-miscible solvents are
presented above in (II)(f). In one embodiment, the weight/weight
ratio of solvent to compound 22 may range from about 2:1 to about
50:1. In a preferred embodiment, the weight/weight ratio of solvent
to compound 22 may range from about 2:1 to about 5:1.
[0129] The reaction may be conducted at a temperature that ranges
from about 20.degree. C. to about 110.degree. C. In a preferred
embodiment, the temperature of the reaction may range from about
35.degree. C. to about 85.degree. C. The reaction may be performed
under hydrogen. The hydrogen pressure may range from about 1 psi to
about 200 psi, and more preferably from about 20 psi to about 80
psi.
[0130] The reaction generally is allowed to proceed for a
sufficient period of time until the reaction is complete, as
determined by chromatography (e.g., HPLC). Typically, the amount of
compound 22 remaining in the mixture may be less than about 5%.
[0131] The yield of compound 23 may range from about 60% to about
90%. In one embodiment, the yield of compound 23 may range from
about 60% to about 70%. In another embodiment, the yield of
compound 23 may range from about 70% to about 80%. In still another
embodiment, the yield of compound 23 may range from about 80% to
about 90%.
(h) Step H: Conversion of Compound 23 to Compound 24
[0132] In Step H of Reaction Scheme 1, compound 23 is first
contacted with a demethylating agent and then contacted with a
proton acceptor to form compound 24. Non-limiting examples of
suitable demethylating agents include BBr.sub.3, BCl.sub.3, HBr,
methionine/MeSO.sub.3H, aluminum bromide, and aluminum chloride
ethanethiol. In a preferred embodiment, the demethylating agent may
be BBr.sub.3 or HBr. The amount of demethylating agent contacted
with compound 23 may vary. In one embodiment, the molar/molar ratio
of compound 23 to demethylating agent may range from about 1:5 to
about 1:20. In another embodiment, the molar/molar ratio of
compound 23 to demethylating agent may range from about 1:3 to
about 1:12. In a preferred embodiment, the molar/molar ratio of
compound 23 to demethylating agent may range from about 1:2 to
about 1:4.
[0133] Contact with the demethylating agent may be conducted in the
presence of an organic solvent. Examples of suitable organic
solvents are presented above in (II)(b). In a preferred embodiment,
the organic solvent may be chloroform. In general, the
weight/weight ratio of solvent to compound 23 may range from about
2:1 to about 50:1. Preferably, the weight/weight ratio of solvent
to compound 23 range from about 5:1 to about 15:1. The reaction may
be conducted at a temperature that ranges from about -20.degree. C.
to about 120.degree. C. In embodiments in which the demethylating
agent is BBr.sub.3, the temperature of the reaction may range from
about 0.degree. C. to about 30.degree. C. And in embodiments in
which the demethylating agent is HBr, the temperature of the
reaction may range from about 90.degree. C. to about 105.degree. C.
The reaction is preferably performed under ambient pressure.
[0134] The reaction further comprises contact with a proton
acceptor. For this, a protic solvent may be added to the reaction
mixture, whereby organic and aqueous phases are formed. Suitable
protic solvents are presented above in (II)(a). In a preferred
embodiment, the protic solvent may be water. In general, the
weight/weight ratio of protic solvent to compound 23 may range from
about 3:1 to about 50:1, or more preferably from about 5:1 to about
20:1. The proton acceptor may be added to the aqueous phase of the
reaction mixture such that pH of the mixture ranges from about pH 7
to about pH 12, or more preferably, from about pH 8 to about pH 10.
In general, the proton acceptor will generally have a pKa of
greater than about 8. Examples of suitable proton acceptors include
weak bases such as NH.sub.4OH, NaHCO.sub.3, KHCO.sub.3, and
Na.sub.2CO.sub.3, as well as proton acceptors presented above in
(II)(b). In a preferred embodiment, the proton acceptor may be
sodium hydroxide (NaOH). The molar/molar ratio of compound 23 to
proton acceptor may range from about 1:5 to about 1:100, or more
preferably from about 1:15 to about 1:30. Contact with the proton
acceptor may be conducted at a temperature that ranges from about
0.degree. C. to about 110.degree. C., or more preferably from about
20.degree. C. to about 80.degree. C. The reaction is preferably
performed under ambient pressure. Typically, the reaction is
allowed to proceed for a sufficient period of time until the
reaction is complete, as determined by chromatography (e.g.,
HPLC).
[0135] The yield of compound 24 may range from about 60% to about
90%. In one embodiment, the yield of compound 24 may range from
about 60% to about 70%. In another embodiment, the yield of
compound 24 may range from about 70% to about 80%. In still another
embodiment, the yield of compound 24 may range from about 80% to
about 90%.
(III) Process for Preparing Compound 21a and Compound 21
[0136] A further aspect of the invention provides a process for
preparing compound 21, wherein an intermediate compound comprising
Formula 21a is formed. The process comprises contacting compound 20
with YX to form compound 21a, which is then hydrolyzed to form
compound 21. For the purposes of illustration, Reaction Scheme 2
depicts the preparation of compound 21a and compound 21:
##STR00020##
[0137] wherein: [0138] R.sup.1 and R.sup.2 are independently
selected from the group consisting of hydrogen, OH, NH.sub.2, SH,
CF.sub.3, hydrocarbyl, substituted hydrocarbyl, alkyl ketal, alkyl
thiol ketal, and alkyl dithiol ketal, wherein when R.sup.1 and
R.sup.2 are different they form an epimeric pair, and wherein
R.sup.1 and R.sup.2 together may form a group selected from the
group consisting of .dbd.O, .dbd.S, cycloalkyl ketal, cycloalkyl
thiol ketal, and cycloalkyl dithiol ketal; [0139] R.sup.3 is
selected from the group consisting of hydrogen, halogen, OH,
NH.sub.2, CN, CF.sub.3, SO.sub.2R.sup.8, hydrocarbyl, and
substituted hydrocarbyl; [0140] R.sup.4 and R.sup.5 are
independently selected from the group consisting of
--(CH.sub.2).sub.nCH.sub.3, and CH.sub.3; [0141] R.sup.8 is
selected from the group consisting hydrocarbyl and substituted
hydrocarbyl; [0142] X is halogen; [0143] Y is selected from the
group consisting of an aryl group, a benzyl group, an acyl group, a
formyl ester, an alkoxycarbonyl group, a benzyloxycarbonyl group,
an alkylamidocarbonyl group, a trialkylsilyl group, an
alkylsulfonyl group, and an aryl sulfonyl group; [0144] YX is
selected from the group consisting of R.sub.mSiX, POX.sub.3,
(RCO).sub.2O, RCOX, RSO.sub.2X, and (RSO.sub.2).sub.2O; [0145] m is
an integer from 1 to 3; and [0146] n is an integer from 1 to 8.
[0147] In a preferred iteration of this embodiment, the
constituents of the reaction comprise: [0148] R.sup.1, R.sup.2, and
R.sup.3 are each hydrogen; [0149] R.sup.4 and R.sup.5 are each
CH.sup.3; and [0150] YX is selected from the group consisting of
(CH.sub.3).sub.3SiCl, POCl.sub.3, (CH.sub.3CO).sub.2O,
CH.sub.3COCl, CH.sub.3SO.sub.2Cl, CH.sub.3CH.sub.2CO.sub.2Cl, and
(CH.sub.3SO.sub.2).sub.2O; [0151] X is bromine; and [0152] Y is
selected from the group consisting of --Si(CH.sub.3).sub.3,
--COCH.sub.3, --CO.sub.2CH.sub.2CH.sub.3, and
--SO.sub.2CH.sub.3.
(a) Step A: Conversion of Compound 20 to Compound 21a
[0153] In Step A of Reaction Scheme 2, compound 20 is contacted
with YX to form compound 21a. Reagent YX is as defined above. In a
preferred embodiment, YX may be (CH.sub.3).sub.3SiCl, CH.sub.3COCl,
CH.sub.3SO.sub.2Cl, or CH.sub.3CH.sub.2CO.sub.2Cl. In one exemplary
embodiment, YX may be (CH.sub.3).sub.3SiCl, and Y may be
--Si(CH.sub.3).sub.3. In another exemplary embodiment, YX may be
CH.sub.3COCl, and Y may be --COCH.sub.3. In a further exemplary
embodiment, YX may be CH.sub.3SO.sub.2Cl, and Y may be
--SO.sub.2CH.sub.3. In yet another exemplary embodiment, YX may be
CH.sub.3CH.sub.2CO.sub.2Cl, and Y may be
--CO.sub.2CH.sub.2CH.sub.3. The molar/molar ratio of compound 20 to
YX can and will vary. In one embodiment, the molar/molar ratio of
compound 20 to YX may range from about 1:1 to about 1.50. In
another embodiment, the molar/molar ratio of compound 20 to YX may
range from about 1:1.2 to about 1:15. In a preferred embodiment,
the molar/molar ratio of compound 20 to YX may range from about
1:1.5 to about 1:5.
[0154] The reaction may be conducted in the presence of an aprotic
solvent. Examples of suitable aprotic solvents are presented above
in (II)(d). In a preferred embodiment, the aprotic solvent is
acetonitrile. In one embodiment, the weight/weight ratio of solvent
to compound 20 may range about 2:1 to about 50:1. In another
embodiment, the weight/weight ratio of solvent to compound 20 may
range about 3:1 to about 40:1. In a preferred embodiment, the
weight/weight ratio of solvent to compound 20 may range from about
5:1 to about 20:1.
[0155] The temperature of the reaction may range from about
0.degree. C. to about 80.degree. C. In a preferred embodiment, the
temperature of the reaction may range from about 15.degree. C. to
about 35.degree. C. The reaction is preferably performed under
ambient pressure.
[0156] Typically, the reaction is allowed to proceed for a
sufficient period of time until the reaction is complete, as
determined by chromatography (e.g., HPLC), and the amount of
compound 20 remaining in the mixture may be less than about 5%.
[0157] The yield of compound 21a may range from about 60% to about
90%. In one embodiment, the yield of compound 21a may range from
about 60% to about 70%. In another embodiment, the yield of
compound 21a may range from about 70% to about 80%. In still
another embodiment, the yield of compound 21a may range from about
80% to about 90%.
(b) Step B: Conversion of Compound 21a to Compound 21
[0158] Step B of Reaction Scheme 2 comprises hydrolysis of compound
21a to form compound 21. Specifically, compound 21a is deprotected
by reaction with an aqueous solution to form compound 21. In a
preferred embodiment, the aqueous solution may be water or a
solution of ammonium hydroxide. In general, the pH of the aqueous
solution may range from about pH 7 to about pH 12, or more
preferably from about pH 8 to about pH 10. The weight/weight ratio
of compound 21a to aqueous solution may range from 1:1 to about
1:50, preferably from about 1:1.5 to about 1:20, or more preferably
from about 1:2 to about 1:8.
[0159] The reaction may be conducted at a temperature that ranges
from about 0.degree. C. to about 100.degree. C. In a preferred
embodiment, the temperature of the reaction may range from about
10.degree. C. to about 50.degree. C. The reaction is preferably
performed under ambient pressure. The reaction generally is allowed
to proceed for a sufficient period of time until the reaction is
complete, as determined by chromatography (e.g., HPLC). Typically,
the amount of compound 21a remaining in the mixture may be less
than about 5%.
[0160] The yield of compound 21 may range from about 60% to about
90%. In one embodiment, the yield of compound 21 may range from
about 60% to about 70%. In another embodiment, the yield of
compound 21 may range from about 70% to about 80%. In still another
embodiment, the yield of compound 21 may range from about 80% to
about 90%.
(IV) Process for the Preparation of Compound 25s and Compound
24s
[0161] Still another aspect of the invention encompasses a process
for the preparation of compound 24s, wherein an intermediate
compound comprising Formula 25s is formed. The process comprises
contacting compound 23s with a demethylating agent to form compound
25s, which is then contacted with a proton acceptor to form
compound 24s, as depicted in Reaction Scheme 3:
##STR00021##
[0162] wherein: [0163] R.sup.1 and R.sup.2 are independently
selected from the group consisting of hydrogen, OH, NH.sub.2, SH,
CF.sub.3, hydrocarbyl, substituted hydrocarbyl, alkyl ketal, alkyl
thiol ketal, and alkyl dithiol ketal, wherein when R.sup.1 and
R.sup.2 are different they form an epimeric pair, and wherein
R.sup.1 and R.sup.2 together may form a group selected from the
group consisting of =O, .dbd.S, cycloalkyl ketal, cycloalkyl thiol
ketal, and cycloalkyl dithiol ketal; [0164] R.sup.3 is selected
from the group consisting of hydrogen, halogen, OH, NH.sub.2, CN,
CF.sub.3, SO.sub.2R.sup.8, hydrocarbyl, and substituted
hydrocarbyl; [0165] R.sup.6 is selected from the group consisting
of hydrogen, an alkyl group, a cycloalkylmethyl group, an aryl
group, a benzyl group, and C(O).sub.nR.sup.7; [0166] R.sup.7 is
selected from the group consisting of an alkyl group, an aryl
group, and a benzyl group; [0167] R.sup.8 is selected from the
group consisting hydrocarbyl and substituted hydrocarbyl; [0168] X
is halogen; and [0169] n is an integer from 1 to 2.
[0170] In a preferred iteration, the constituents of the reaction
comprise: [0171] R.sup.1, R.sup.2, and R.sup.3 are each hydrogen;
[0172] R.sup.6 is selected from the group consisting of hydrogen,
CH.sub.3, --COCH.sub.3, and --CO.sub.2CH.sub.2CH.sub.3; and [0173]
X is bromine.
(a) Step A: Conversion of Compound 23s to Compound 25s
[0174] In Step A of Reaction Scheme 3, compound 23s is contacted
with a demethylating agent to form compound 25s. Non-limiting
examples of suitable demethylating agents include BBr.sub.3,
BCl.sub.3, HBr, methionine/MeSO.sub.3H, aluminum bromide, and
aluminum chloride ethanethiol. In a preferred embodiment, the
demethylating agent may be BBr3 or HBr. In general, the molar/molar
ratio of compound 23 to demethylating agent may range from about
1:5 to about 1:20. In a preferred embodiment, the molar/molar ratio
of compound 23 to demethylating agent may range from about 1:3 to
about 1:12. In an exemplary embodiment, the molar/molar ratio of
compound 23 to demethylating agent may range from about 1:2 to
about 1:4.
[0175] Contact with the demethylating agent may be conducted in the
presence of an organic solvent. Examples of suitable organic
solvents are presented above in (II)(b). In a preferred embodiment,
the organic solvent may be chloroform. Typically, the weight/weight
ratio of solvent to compound 23 will range from about 2:1 to about
50:1. In a preferred embodiment, the weight/weight ratio of solvent
to compound 23 range from about 5:1 to about 15:1.
[0176] In general, the reaction may be conducted at a temperature
that ranges from about -20.degree. C. to about 120.degree. C. In
embodiments in which the demethylating agent is BBr.sub.3, the
temperature of the reaction may range from about 0.degree. C. to
about 30.degree. C. And in embodiments in which the demethylating
agent is HBr, the temperature of the reaction may range from about
90.degree. C. to about 105.degree. C. The reaction is preferably
performed under ambient pressure.
[0177] The reaction generally is allowed to proceed for a
sufficient period of time until the reaction is complete, as
determined by chromatography (e.g., HPLC). Typically, the amount of
compound 23s remaining in the mixture may be less than about
5%.
[0178] The yield of compound 25s may range from about 60% to about
90%. In one embodiment, the yield of compound 25s may range from
about 60% to about 70% . In another embodiment, the yield of
compound 25s may range from about 70% to about 80%. In still
another embodiments the yield of compound 25s may range from about
80% to about 90%.
(b) Step B forward: Conversion of Compound 25s to Compound 24s
[0179] Step B of Reaction Scheme 3 comprises contacting compound
25s with a proton acceptor to form compound 24s. Typically, the
proton acceptor will generally have a pKa of greater than about 8.
Examples of suitable proton acceptors include weak bases such as
NH.sub.4OH, NaHCO.sub.3, KHCO.sub.3, and Na.sub.2CO.sub.3, as well
as proton acceptors presented above in (II)(b). In a preferred
embodiment, the proton acceptor may be sodium hydroxide (NaOH).
Stated another way, upon addition of the proton acceptor, the pH of
reaction mixture may range from about pH 7 to about pH 12, or more
preferably, from about pH 8 to about pH 10. In one embodiment, the
molar/molar ratio of compound 25s to proton acceptor may range from
about 1:5 to about 1:100. In another embodiment the molar/molar
ratio of compound 25s to proton acceptor may range from about 1:10
to about 1:50. In a preferred embodiment, the molar/molar ratio of
compound 25s to proton acceptor range from about 1:15 to about
1:30.
[0180] The reaction may be performed in the presence of a protic
solvent. Suitable protic solvents are presented above in (II)(a).
In a preferred embodiment, the protic solvent may be water. The
weight/weight ratio of protic solvent to compound 25s may range
from about 3:1 to about 50:1, or more preferably from about 5:1 to
about 20:1.
[0181] The temperature of the reaction may range from about
0.degree. C. to about 110.degree. C. In a preferred embodiment, the
temperature of the reaction may range from about 20.degree. C. to
about 80.degree. C. The reaction is preferably performed under
ambient pressure.
[0182] The reaction generally is allowed to proceed for a
sufficient period of time until the reaction is complete, as
determined by chromatography (e.g., HPLC). Typically, the amount of
compound 25s remaining in the mixture may be less than about
5%.
[0183] The yield of compound 24s may range from about 60% to about
90%. In one embodiment, the yield of compound 24s may range from
about 60% to about 70%. In another embodiment, the yield of
compound 24s may range from about 70% to about 80%. In still
another embodiment, the yield of compound 24s may range from about
80% to about 90%.
(c) Step B Reverse: Conversion of Compound 24s to Compound 25s
[0184] Step B of Reaction Scheme 3 also comprises the conversion of
compound 24s to compound 25s. For this, compound 24s is contacted
with a demethylating agent to form compound 25s. Examples of
suitable demethylating agents are presented above in (IV)(a). The
molar/molar ratio of compound 24s to demethylating agent may range
from about 1:5 to about 1:20, preferably from about 1:3 to about
1:12, or more preferably from about 1:2 to about 1:4. Contact with
the demethylating agent may be conducted in the presence of an
organic solvent. Examples of suitable organic solvents are
presented above in (II)(b). In a preferred embodiment, the organic
solvent may be chloroform. The weight/weight ratio of solvent to
compound 24s will range from about 2:1 to about 50:1, or preferably
from about 5:1 to about 15:1.
[0185] The reaction may be conducted at a temperature that ranges
from about -20.degree. C. to about 120.degree. C. The reaction is
preferably performed under ambient pressure. The reaction generally
is allowed to proceed for a sufficient period of time until the
reaction is complete, as determined by chromatography (e.g., HPLC).
Typically, the amount of compound 24s remaining in the mixture may
be less than about 5%.
[0186] The yield of compound 25s may range from about 60% to about
90%. In one embodiment, the yield of compound 25s may range from
about 60% to about 70%. In another embodiment, the yield of
compound 25s may range from about 70% to about 80%. In still
another embodiment, the yield of compound 25s may range from about
80% to about 90%.
(V) Compounds Prepared from Compound 24
[0187] Compounds corresponding to compound 24 may be end products
themselves, or intermediates that may be further derivatized in one
or more steps to yield further morphinan intermediates or end
products. By way of non-limiting example, one or more compounds
corresponding to compound 24 may be used in processes to produce a
compound selected from the group consisting of nalbuphine,
nalmefene, naloxone, naltrexone, naltrexone methobromide,
3-O-methyl naltrexone, .alpha.- or .beta.-naltrexol, .alpha.- or
.beta.-naloxol, .alpha.- or .beta.-naltrexamine, and the salts,
intermediates, and analogs thereof. General reaction schemes for
the preparation of such commercially valuable morphinans are
disclosed, among other places, in U.S. Pat. No. 4,368,326 to Rice,
the entire disclosure of which is hereby incorporated by reference
herein. Additionally, in some embodiments, the 6-ketone of compound
24 may be reduced to 6-.alpha.-OH, 6-.beta.-OH, 6-.alpha.-NH.sub.2,
or 6-.beta.-NH.sub.2.
DEFINITIONS
[0188] To facilitate understanding of the invention, several terms
are defined below.
[0189] The term "acyl," as used herein alone or as part of another
group, denotes the moiety formed by removal of the hydroxy group
from the group COOH of an organic carboxylic acid, e.g., RC(O),
wherein R is R.sup.1, R.sup.1O--, R.sup.1R.sup.2N--, or R.sup.1S--,
R.sup.1 is hydrocarbyl, heterosubstituted hydrocarbyl, or
heterocyclo, and R.sup.2 is hydrogen, hydrocarbyl or substituted
hydrocarbyl.
[0190] The term "alkyl" as used herein describes groups which are
preferably lower alkyl containing from one to eight carbon atoms in
the principal chain and up to 20 carbon atoms. They may be straight
or branched chain or cyclic and include methyl, ethyl, propyl,
isopropyl, butyl, hexyl and the like.
[0191] The term "alkenyl" as used herein describes groups which are
preferably lower alkenyl containing from two to eight carbon atoms
in the principal chain and up to 20 carbon atoms. They may be
straight or branched chain or cyclic and include ethenyl, propenyl,
isopropenyl, butenyl, isobutenyl, hexenyl, and the like. "Allyl"
refers to an alkenyl group comprising a vinyl group attached to a
methylene group.
[0192] The term "alkynyl" as used herein describes groups which are
preferably lower alkynyl containing from two to eight carbon atoms
in the principal chain and up to 20 carbon atoms. They may be
straight or branched chain and include ethynyl, propynyl, butynyl,
isobutynyl, hexynyl, and the like.
[0193] The term "aromatic" as used herein alone or as part of
another group denotes optionally substituted homo- or heterocyclic
aromatic groups. These aromatic groups are preferably monocyclic,
bicyclic, or tricyclic groups containing from 6 to 14 atoms in the
ring portion. The term "aromatic" encompasses the "aryl" and
"heteroaryl" groups defined below.
[0194] The term "aryl" as used herein alone or as part of another
group denote optionally substituted homocyclic aromatic groups,
preferably monocyclic or bicyclic groups containing from 6 to 12
carbons in the ring portion, such as phenyl, biphenyl, naphthyl,
substituted phenyl, substituted biphenyl or substituted naphthyl.
Phenyl and substituted phenyl (such as a benzyl group) are the more
preferred aryl groups.
[0195] The terms "halogen" or "halo" as used herein alone or as
part of another group refer to chlorine, bromine, fluorine, and
iodine. The term "heteroatom" shall mean atoms other than carbon
and hydrogen.
[0196] The terms "heterocyclo" or "heterocyclic" as used herein
alone or as part of another group denote optionally substituted,
fully saturated or unsaturated, monocyclic or bicyclic, aromatic or
non-aromatic groups having at least one heteroatom in at least one
ring, and preferably 5 or 6 atoms in each ring. The heterocyclo
group preferably has 1 or 2 oxygen atoms and/or 1 to 4 nitrogen
atoms in the ring, and is bonded to the remainder of the molecule
through a carbon or heteroatom. Exemplary heterocyclo groups
include heteroaromatics as described below. Exemplary substituents
include one or more of the following groups: hydrocarbyl,
substituted hydrocarbyl, hydroxy, protected hydroxy, acyl, acyloxy,
alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino, cyano,
ketals, acetals, esters and ethers.
[0197] The terms "hydrocarbon" and "hydrocarbyl" as used herein
describe organic compounds or radicals consisting exclusively of
the elements carbon and hydrogen. These moieties include alkyl,
alkenyl, alkynyl, and aryl moieties. These moieties also include
alkyl, alkenyl, alkynyl, and aryl moieties substituted with other
aliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenaryl
and alkynaryl. Unless otherwise indicated, these moieties
preferably comprise 1 to 20 carbon atoms.
[0198] The "substituted hydrocarbyl" moieties described herein are
hydrocarbyl moieties which are substituted with at least one atom
other than carbon, including moieties in which a carbon chain atom
is substituted with a hetero atom such as nitrogen, oxygen,
silicon, phosphorous, boron, sulfur, or a halogen atom. These
substituents include halogen, heterocyclo, alkoxy, alkenoxy,
aryloxy, hydroxy, protected hydroxy, acyl, acyloxy, nitro, amino,
amido, nitro, cyano, ketals, acetals, esters and ethers.
[0199] When introducing elements of the present invention or the
preferred embodiments(s) thereof, the articles "a", "an", "the" and
"said" are intended to mean that there are one or more of the
elements. The terms "comprising", "including" and "having" are
intended to be inclusive and mean that there may be additional
elements other than the listed elements.
[0200] As various changes could be made in the above compounds and
processes without departing from the scope of the invention, it is
intended that all matter contained in the above description and in
the examples given below, shall be interpreted as illustrative and
not in a limiting sense.
EXAMPLES
[0201] The following examples illustrate the synthesis of
noroxymorphone, as depicted in the following reaction scheme:
##STR00022## ##STR00023##
Example 1
Synthesis of Compound 14 from Compound 13
[0202] Compound 13 (107 g; assayed 82%; 88 g actual; 0.224 mole)
and methanol (MeOH) (850 mL) were combined and stirred for
.about.15 minutes. After filtration to remove the insoluble
materials, the solid was washed with methanol (200 mL). The
combined filtrate and wash were placed in a 2 L flask under a
nitrogen atmosphere and 48% hydrobromic acid (HBr) (88 mL) was
slowly added while keeping the temperature below 40.degree. C. The
reaction mixture was distilled until a pot temperature of
75.degree. C. was attained. The mixture was refluxed for 3-5 hours.
The reaction was determined to be complete when HPLC analysis
indicated less than 2% of compound 13 remained. Water (850 mL) was
added and the mixture was heated to .about.60-70.degree. C. until
all the solids dissolved. The mixture was cooled to 55-60.degree.
C. and chloroform was added (150 mL). The phases were stirred,
allowed to settle, and then separated. To the aqueous phase was
added chloroform (50 mL), the phases were stirred, allowed to
settle, and then separated. Water (82 mL), methanol (18 mL), and 5
drops of 48% HBr were added to the combined chloroform extracts.
The phases were stirred, allowed to settle, and then separated. The
chloroform phases contained .about.8 gm/L of compound 14. The
aqueous phases from the last two extractions were combined and
cooled to 0-10.degree. C. with stirring for 1-2 hours. The solids
were separated by filtration and the cake was washed with water
(100 mL). The solid was dried at 60.degree. C. under partial vacuum
with a nitrogen sweep. The drying time was .about.72 hours. The
combined liquors contained .about.8 g/L of compound 14. Table 1
presents the results from two reactions.
TABLE-US-00003 TABLE 1 Synthesis of Compound 14. Weight Percent W/W
Expt # Yield Yield Assay 1 78 g 78% 96.9% 2 73 g 73% 95.0%
Example 1a
Another Synthesis of Compound 14 from Compound 13
[0203] Compound 13 (73.2 g; 0.19 moles; 96 w/w %) and anhydrous
methanol (250 mL) were added to a three-necked round bottom flask
equipped with a mechanical stirrer. The mixture was cooled to
5.degree. C. and 48% hydrobromic acid (150.2 g; 1.86 moles) was
added dropwise over a period of an hour. The addition funnel was
removed and replaced with a short place distillation set-up. The
reaction was warmed slowly to reflux (set point 85.degree. C., pot
temperature 75.degree. C). The reaction was refluxed for 4 hours
and 125 mL of solvent was distilled off. Liquid chromatography
revealed that approximately 1% of compound 13 remained.
[0204] The reaction was cooled to 50.degree. C. and 125 mL of
distilled water was added. After stirring for 5 min, the aqueous
phase was extracted with chloroform (3.times.100 mL) at a
temperature between 40.degree. C. and 50.degree. C. The organic
phase was discarded, and 3 ml of 48% HBr was added to the aqueous
phase. The mixture was stirred until it reached room temperature,
and then it was cooled to 0.degree. C. After standing at 0.degree.
C. for 2 hours, crystals formed. The crystals were removed by
filtration, washed with 25 mL of cold water, and dried. The
filtrate was cooled again to 0.degree. C., the crystals were
filtered, and washed with water. This process was repeated two more
times, for a total of four crops of crystals. Weight of compound
14, 55.6 g; yield, 81.8%; assay, 97 w/w %.
Example 2
Synthesis of Compound 16 from Compound 14
[0205] Compound 14 HBr salt (50 g; assayed .about.95%; 47.5 g
actual; 0.16 mole), chloroform (CHCl.sub.3) (1 L), and 48% HBr (3.5
mL) were added to a glass reactor. The mixture was stirred and
cooled to -45 to -55.degree. C. Bromine (20.2 g; 0.126 mole) was
diluted to 500 mL with chloroform, and the solution was placed in
an addition funnel. Bromine solution (450 mL) was added to the
reaction mixture over a 30 minute period at -50.degree. C. HPLC
indicated that 9.8% of unreacted compound 14 remained. Additional
bromine solution (30 mL) was added to the reaction mixture. HPLC
indicated that 2.9% of unreacted compound 14 remained, but the over
bromination products were growing. The reaction was allowed to warm
to .about.10.degree. C., and 4 N sodium hydroxide (1 L) was added.
The mixture was stirred for 15 minutes, the phases were allowed to
settle, and then separated. 1N sodium hydroxide (1 L) was added,
the phases were stirred, allowed to settle, and then separated.
Water (1 L) was added, the phases were stirred, allowed to settle,
and then separated. The three aqueous extracts were tested by HPLC
and no 16 was found, but the solution did contain unwanted
impurities. The organic solution was then evaporated to give dry 16
base. The results are presented in Table 2.
TABLE-US-00004 TABLE 2 Synthesis of Compound 16. W/W W/W Weight
Percent Assay Assay Expt # Yield Yield (16) (14) 1 34.1 g 88.1%
72.7% 5.4% 2 33.9 g 87.6% * * 3** 21.0 g 68.0% 81.0% 5.0% * Assay
not run **Starting material was 40 g of compound 14
[0206] The three samples of 16 were combined. Anhydrous ethanol
(1.25 L), water (0.25 L), and 48% HBr (55 mL) were added to the
samples. The mixture was heated to boiling (78-80.degree.) and
stirred for one hour. All the solids dissolved and 400 mL of
solvent was distilled. The solution was cooled to allow
crystallization to begin. The slurry was cooled to 0-10.degree. C.
and stirred for two hours. The solids were separated by filtration,
washed with anhydrous ethanol (100 mL) and then dried at 60.degree.
C. under partial vacuum. The yield of 16 HBr salt was 62.7 g. HPLC
analysis indicated the purity was better than the existing
standard. The filtrates (i.e., mother liquor and wash liquor)
contained .about.12 g of compound 16.
[0207] To prepare the HBr salt of 16, four additional samples of 16
(containing 84.8 g) were combined in a 2 L flask. Anhydrous ethanol
(1.25 L), water (100 mL), and 48% HBr (55 mL) were added. The
mixture was heated to reflux and .about.400 mL of solvent was
removed by distillation. The mixture was cooled to 0-5.degree. C.
and stirred for one hour. The slurry was filtered, the cake was
washed with anhydrous ethanol (100 mL) and the solids dried at
60.degree. C. in a vacuum oven. A yield of 62.7 g of 16.HBr was
obtained at a HPLC purity of 99.4% area. A second crop of 7.5 g of
16.HBr was obtained from work-up of the filtrates. HPLC profile of
99.3% area was obtained.
Example 2a
Additional Syntheses of Compound 16
[0208] Additional reactions were performed in which compound 14 was
contacted with HBr in the presence of mixtures of acetic acid and
chloroform. These experiments revealed that the temperature of the
reaction could be increased to between 0.degree. C. and 5.degree.
C. upon addition of acetic acid to the organic solvent.
Furthermore, the through-put of compound 16 increased. For example,
the through-put was increased by about 4- to 5-fold when a 50:50
mixture of acetic acid and chloroform was used (see Table 3).
Although 100% acetic acid had the best through-put, the isolated
product had a low yield (60%).
TABLE-US-00005 TABLE 3 Solvent Composition, Reaction Temperature,
and Yield. Wt Area % compound Add Wt to vol % compound 14 (g)
Temperature Solvent solvent recovery 16 Note 1.50 g 0-5.degree. C.
100% CHCl.sub.3 1 to 50 82% 84.5% 1 1.33 g 0-5.degree. C. 5%
HOAc/CHCl.sub.3 1 to 30 83% 77.4% 1 1.92 g 0-5.degree. C. 10%
HOAc/CHCl.sub.3 1 to 25 85% 83.9% 2 1.05 g 0-5.degree. C. 25%
HOAc/CHCl.sub.3 1 to 20 84% 80.0% 2 2.09 g 0-5.degree. C. 50%
HOAc/CHCl.sub.3 1 to 10 88% 82.9% 2 2.23 g room 100% HOAc 1 to 7.5
90% 82.8% 2 temp Note: 1 = Aqueous NaOH added dropwise into
reaction mixture. 2 = Reaction mixture added dropwise into aqueous
NaOH.
[0209] Compound 14.HBr (2.09 g; 4.7 mmol), 50% glacial acetic acid
in chloroform (21 mL) and 2 drops of 48% HBr were added to a
three-necked round bottom flask. The mixture was cooled to
0-5.degree. C. and bromine (0.376 g; 2.3 mmol) was added dropwise.
The reaction was stirred for 50 minutes at 0.degree. C. Then,
bromine (0.376 g; 2.3 mmol) was added dropwise, and the reaction
was stirred for 15 minutes at 5.degree. C. Sodium hydroxide (12.0
g, 0.30 moles) was added to 100 mL of distilled water in a separate
flask, and the mixture was cooled to 5.degree. C. The reaction
mixture was added dropwise to the NaOH solution over a one hour
period and the temperature was kept below 10.degree. C. The
reaction mixture was warmed to room temperature. The mixture was
transferred to a separatory funnel, and extracted with chloroform
(3.times.10 mL). The organic phases were combined, dried over
anhydrous MgSO.sub.4 (2 g), filtered, and evaporated. Purified
compound 16 (HBr salt, 2.0 g; 81% yield, 99 w/w % assay) was
obtained from crystallization from methanol (5 mL), distilled water
(5 mL), and 1 drop of 48% HBr. The crystals were isolated by
filtration and were dried at 60.degree. C. for 48 hr.
Example 3
Synthesis of Compound 19 from Compound 16
[0210] A 125 mL three-neck flask was equipped with a thermometer, a
dropping funnel for addition of bromine (Br.sub.2). Another
dropping funnel connected to the top of condenser was used to
collect the distilled solvent. The compound 16.HBr (5.50 g) was
suspended in MeOH/CH(OMe).sub.3 (20 mL/20 mL) at room temperature.
Sulfuric acid (H.sub.2SO.sub.4, 1.0 mL) was added (pH=0.about.0.5).
The suspension was heated to reflux for 2 minutes, forming a
solution at 55.degree. C. Solvent (.about.20 mL) was removed by
distillation at 88.degree. C. in an oil bath for 15 minutes.
Dichloroethane (bp: 83.degree. C., 20 mL) was added. The mixture
was heated over the 88.degree. C. oil bath to distill off .about.10
mL solvent over 10 minutes. H.sub.2SO.sub.4 (0.25 mL) was added
(pH=0.about.1). A solution of Br.sub.2 in CHCl.sub.3 (0.70 mmol/mL,
19.6 mL, 1.1 eq, was diluted to 40 mL with CHCl.sub.3) was added
dropwise over 25 minutes. H.sub.2SO.sub.4 (0.25 mL) was added. 50 g
of solution was obtained, of which 5 g was taken for another
experiment and the rest of the reaction mixture (45 g) was cooled
to room temperature for the following isolation of 19 acid
salt.
[0211] The reaction mixture was evaporated on a Buchi rotary
evaporator at 40.degree. C. under maximum vacuum. Chloroform
(ethanol free; 50 mL) and water (50 mL) were added to the residue.
This mixture was stirred, allowed to settle, and the phases were
separated. The aqueous phase was extracted twice more with
chloroform (ethanol free; 5 mL). All of the chloroform extracts
were combined and evaporated on the Buchi. Acetone (80 mL) was
added to the evaporation residue and the stirred mixture was warmed
to 45.degree. C. A white precipitate formed after .about.45 sec of
stirring. The mixture was cooled to 0-5.degree. C. and stirred for
30 min. The precipitate was filtered and the solids were washed
with acetone (.about.5 mL). The solids were air dried, and 3.9 g of
19.H.sub.2SO.sub.4 at a HPLC profile of 95.3% area was
recovered.
Example 4
Synthesis of Compound 20 from Compound 19
[0212] The compound, 19.H.sub.2SO.sub.4 (4.9 g), was suspended in
tetrahydrofuran (THF) (50 mL). After flushing with nitrogen,
tert-butoxide (t-BuOK) (7.0 g) was added. The mixture was stirred,
heated at 65.degree. C. for 1.5 h, and then cooled to room
temperature. Water (200 mL) was added under nitrogen with stirring
for 3 h. After the time period, the precipitate was separated by
filtration and washed with water (2.times.30 mL). The wet solid was
dried in flowing air for 2 h. The solid was suspended in
acetonitrile (ACN) and reduced to dryness at 60.degree. C. in
vacuum for 2 h to give 2.85 g of compound 20 as a yellow solid (82%
yield).
Example 5
Synthesis of Compound 21 from Compound 20
[0213] Compound 20 (2.85 g) was suspended in Me.sub.3SiCl/ACN (8.5
m/20 mL) for 1 h. This suspension was added (1 mL each time) to a
solution of Me.sub.3SiCl (8.5 mL) in ACN (40 mL) to form a new
solution. Each aliquot of the suspension dissolved in 2.about.5 min
after addition to the solution. The solution was stirred for
another 30 min and after the complete addition of the suspension.
The solution was then added to 10% NH.sub.4OH (240 mL) and
extracted with CHCl.sub.3 (2.times.50 mL). The organic layers were
washed with water (2.times.100 mL), pumped down to dryness to give
the product, 21, as 2.93 g of solid.
Example 6
Synthesis of Compound 23 from Compound 21
[0214] Compound 21 (.about.2.90 g) was dissolved in 29 mL
HOAc/H.sub.2O (1:1) to form a solution. The solution was cooled to
5.about.10.degree. C. and 32% peracetic acid (CH.sub.3CO.sub.3H)
(in diluted HOAc) was added in three portions. The reaction mixture
was stirred at room temperature for 30 min. Pd--C (5% Pd on carbon,
0.3 g) was added and stirred for 20 min to give a reaction mixture.
HPLC analysis of the mixture revealed that compound 22 was the
major product (>90% area/area). Additional Pd--C (5% Pd on
carbon, 0.3 g) was added to the reaction mixture, which was heated
at 60.degree. C. under hydrogen (60 PSI) and stirred for 2 h. The
reaction mixture was cooled to room temperature and filtered though
.about.10 g of silical gel. The solid was washed with 1% HOAc in
MeOH (50 mL). The filtrate was reduced under vacuum to give an oil,
which was dissolved in CHCl.sub.3 (30 mL). Water (60 mL) was added,
the phases were separated, and the aqueous phase as extracted with
CHCl.sub.3 (30 mL). The combined organic layers were washed with
water (2.times.30 mL) and evaporated to give 1.29 g of the product,
23, as a solid.
Example 7
Synthesis of Compound 24 from Compound 23
[0215] Compound 23 (1.29 g solid) was dissolved in CHCl.sub.3 to
make 13.0 mL of solution. Part of the above solution (9.7 mL,
containing .about.0.98 g 23) was added to a solution of BBr.sub.3
(2.82 mL) in CHCl.sub.3 (10 mL) at 0-5.degree. C. to form a
suspension. The suspension was stirred at room temperature for 3 h,
and 1 mL of the mixture was taken for HPLC sample before work up.
The reaction mixture was stirred for a total of 5 h and then added
to water (40 mL). Nitrogen was bubbled through the CHCl.sub.3 layer
until most of the CHCl.sub.3 was removed by evaporation. The
remaining mixture was washed with ether (3.times.40 mL), and then 4
N NaOH (10 mL) was added to the aqueous layer after extraction. The
solution formed was washed with ether (3.times.40 mL). To the
aqueous layer, HOAc was added until pH=9 (finally adjusted by
adding c-NH.sub.4OH). The solution was reduced to dryness under
vacuum to give a sticky solid. The solid was suspended in 5%
NH.sub.4OH solution (20 mL), stirred for 30 minutes, and filtered.
The solid was re-suspended in MeOH/H.sub.2O (9 ml/6 mL). HOAc (0.4
mL) was added to form a solution. A precipitate formed upon
addition of c-NH.sub.4OH to pH=9. The mixture was stirred at
5.degree. C. for 1 h, and the solid was separated by filtration.
After washing with water and drying in an air-flow overnight, 0.61
g of an off-white solid remained. The solid was dried in high
vacuum at 60.degree. C. for 3 h to give 0.56 g of the product, 24,
as an off-white solid.
* * * * *